There are many promising compounds in development for Alzheimer's disease, based on substantial preclinical evidence supporting efficacy in model systems and acceptable safety data to allow chronic human exposure. Guidance for developing a clinical trial program is often held back by the absence of pharmacokinetic/pharmacodynamic (pK/pD) data to support target engagement within the central nervous system (CNS) and to aid in dose selection. For small molecules that target secretases or other key biochemical pathways in AD, studies involving CSF and plasma sampling in humans are the best way to demonstrate that a drug crosses the blood-brain barrier and engages the relevant target, and to help establish the relationship between blood levels and CNS effects. Repeated sampling through a lumbar CSF catheter over 24-36 hours, and the technique of stable metabolic labeling to measure parameters such as fractional synthesis rate of amyloid beta protein (ABeta), have helped to guide the development of gamma-secretase inhibitors developed by Pharma, but have not been available to biotechnology companies and academic laboratories. To fill this need to increase the efficacy and speed of drug development, continued CSF and plasma sampling and SILK will be established at 6 academic sites with initial proposed studies evaluating 4 candidate drugs for future ADCS Phase II/III trials.